Death receptors and melanoma resistance to apoptosis

Ivanov, Vladimir N.; Bhoumik, Anindita; Ronai, Ze’ev A.

doi:10.1038/sj.onc.1206456

Cited by 199 publications

(158 citation statements)

References 118 publications

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“…The internal strategy of genetic and epigenetic regulation during progression of cancer, based on Darwinian selection, is to suppress death signaling at all levels, including downregulation of transcription of death receptor genes, inhibition of receptor's modification, suppression of translocation of death receptors to the cell surface, elevated mutagenesis in the death domains, the dramatic STAT3/NF-κB-dependent upregulation of expression of apoptotic inhibitors and upregulation of surface expression of decoy receptors, DcR1 and DcR2 [9,34,[43][44][45]. Investigation of natural and pharmacological inhibitors of STAT3 and NF-κB represents a significant and novel tactics in the struggle against cancer.…”

Section: Discussionmentioning

confidence: 99%

“…2 and 3). The well known control of Bcl-xL, Survivin, TRAIL and Fas genes by STAT3 certainly demonstrated its integral role as a regulator of apoptosis in melanomas [9]. An additional important target of RSV in melanoma cells was the activation of the JNK-cJun pathway, which was involved in regulating the expression and turnover of cFLIP [11,13] and the upregulation of sensitivity to TRAIL.…”

Section: Discussionmentioning

confidence: 99%

“…Various attempts have been made to restore high levels of apoptosis in response to treatment for this type of cancer [4][5][6]. One of the key contributors to radio-and chemoresistance of human melanomas is upregulation of transcription factors STAT3 and NF-κB, which control expression of numerous antiapoptotic genes in cancer cells, including cFLIP, cIAP, XIAP, Bcl-xL, Survivin, as well as suppressing proapoptotic genes [7][8][9][10]. On the other hand, via activation of cJun, JNK is involved in the negative regulation of cFLIP (an inhibitor of caspase-8) expression [11,12] and, via activation of E3 ubiquitin-protein ligase Itch, in acceleration of proteasome-dependent cFLIP degradation [13].…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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Although many human melanomas express the death receptors TRAIL-R2/DR5 or TRAIL-R1/ DR4 on cell surface, they often exhibit resistance to exogenous TRAIL. One of the main contributors to TRAIL-resistance of melanoma cells is upregulation of transcription factors STAT3 and NF-κB that control the expression of antiapoptotic genes, including cFLIP and BclxL. On the other hand, the JNK-cJun pathway is involved in the negative regulation of cFLIP (a caspase-8 inhibitor) expression. Our observations indicated that resveratrol, a polyphenolic phytoalexin, decreased STAT3 and NF-κB activation, while activating JNK-cJun that finally suppressed expression of cFLIP and Bcl-xL proteins and increased sensitivity to exogenous TRAIL in DR5-positive melanomas. Interestingly, resveratrol did not increase surface expression of DR5 in human melanomas, while γ-irradiation or sodium arsenite treatment substantially upregulated DR5 expression. Hence, an initial increase in DR5 surface expression (either by γ-irradiation or arsenite), and subsequent downregulation of antiapoptotic cFLIP and Bcl-xL (by resveratrol), appear to constitute an efficient approach to reactivate apoptotic death pathways in TRAIL-resistant human melanomas. In spite of partial suppression of mitochondrial function and the mitochondrial death pathway, melanoma cells still retain the potential to undergo the DR5-mediated, caspase-8-dependent death pathway that could be accelerated by either an increase in DR5 surface expression or suppression of cFLIP. Taken together, these results suggest that resveratrol, in combination with TRAIL, may have a significant efficacy in the treatment of human melanomas.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Ivanov

Partridge

Johnson

et al. 2008

Experimental Cell Research

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“…Malignant melanomas show impaired ability to undergo programmed cell death (apoptosis) in response to a wide range of external stimuli, conferring them with a selective advantage for progression and metastasis as well as resistance to therapy (Ivanov et al, 2003;Gong et al, 2005;Li et al, 2005). In this study, we observed increased transcription of anti-apoptotic genes in the melanoma compared with normal samples (Table 5), including BCL-2, an integral outer mitochondrial membrane protein that blocks cell death by controlling mitochondrial membrane permeability and prevents translocation of pro-apoptotic caspases (Chandra et al, 2002) that was upregulated by 2.5-fold in melanoma compared with normal liver, but was unchanged in the rest of the samples.…”

Section: Differential Gene Expression In Melanoma Compared With Normamentioning

confidence: 99%

Gene expression in Sinclair swine with malignant melanoma

Okomo-Adhiambo

Rink

Rauw

et al. 2012

Animal

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Sinclair swine develop an aggressive form of melanoma, which, in many cases, spontaneously regresses after a complete metastatic phase. We used Affymetrix GeneChip R Porcine Genome Arrays consisting of 24 123 probe sets to compare gene expression in white blood cells (WBCs) and various tissues including the liver, lungs, inguinal lymph nodes and spleen harvested from a Sinclair piglet afflicted by melanoma at birth and exhibiting metastatic lesions at weaning (6 weeks) with those from a full-sibling piglet that showed no incidence of melanoma at birth and weaning. The highest number (3489; ,14%) of significantly upregulated transcripts (fold change in gene expression >2.0 and t-test P-value r0.05) was observed in the liver, while the spleen exhibited the lowest number of upregulated transcripts (528; ,2%). Among significantly downregulated genes, the highest numbers were observed in the inguinal lymph nodes (3651; ,15%) and the least in WBCs (730; ,3%). Differentially expressed transcripts included genes involved in melanoma pathogenesis including SILV, TYR and RAB28. SILV was over-expressed 784-, 430-and 164-fold, while TYR was over-expressed 138-, 81-and 28-fold in the liver, lungs and inguinal lymph nodes, respectively. Quantitative real-time RT-PCR (qRT-PCR) confirmed the microarray data of 12 selected differentially expressed sequences. These results suggest that significant changes in gene expression occur during metastasis of malignant melanoma in the Sinclair swine model. In addition, qRT-PCR analysis of the above 12 differentially expressed sequences was carried out on liver samples collected from 22 pigs (12 of which had melanoma during the first 6 weeks of life), and an ANOVA test contrasting absolute RNA expression between pigs with regressing, progressing and without tumors was significant for TYR, TACSTD1, MATP, GPNMB and CYP4A22, with P-values of 0.034, 0.015, 0.007, 0.050 and 0.022, respectively.

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“…Human melanoma, the most aggressive form of the skin cancer, is highly resistant to treatment with γ-irradiation or anticancer drugs and has altered and inhibited apoptotic signaling pathways [13,17]. Furthermore, human melanomas actively suppress the immune system [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells

Ivanov¹,

Hei²

2006

Experimental Cell Research

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Most human melanomas express Fas receptor on the cell surface, and treatment with exogenous Fas Ligand (FasL) efficiently induces apoptosis of these cells. In contrast, endogenous surface expression of FasL is suppressed in Fas-positive melanomas. We report here the use of a combination of sodium arsenite, an inhibitor of NF-κB activation, and NS398, a cyclooxygenase-2 (COX-2) inhibitor, for restoration of the surface FasL expression. We observed a large increase of Fas-mediated apoptosis in Fas-positive melanomas. This was due to induction of FasL surface expression and increased susceptibility to Fas death signaling after arsenite and NS398 treatment. Furthermore, silencing COX-2 expression by specific RNAi also effectively increased surface FasL expression following arsenite treatment. Upregulation of the surface FasL levels was based on an increase in the efficiency of translocation to the cell surface and stabilization of FasL protein on the cell surface, rather than on acceleration of the FasL gene transcription. Data obtained demonstrate that the combination of arsenite with inhibitors of COX-2 may affect the target cancer cells via induction of FasL-mediated death signaling.

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Death receptors and melanoma resistance to apoptosis

Cited by 199 publications

References 118 publications

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

Gene expression in Sinclair swine with malignant melanoma

Dual treatment with COX-2 inhibitor and sodium arsenite leads to induction of surface Fas Ligand expression and Fas-Ligand-mediated apoptosis in human melanoma cells

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